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<article article-type="research-article" dtd-version="1.3" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xml:lang="ru"><front><journal-meta><journal-id journal-id-type="publisher-id">morpho</journal-id><journal-title-group><journal-title xml:lang="ru">Морфологические ведомости</journal-title><trans-title-group xml:lang="en"><trans-title>Morphological newsletter</trans-title></trans-title-group></journal-title-group><issn pub-type="ppub">1812-3171</issn><issn pub-type="epub">2686-8741</issn><publisher><publisher-name>Private Medical University REAVIZ</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.20340/mv-mn.2024.32(4).915</article-id><article-id custom-type="elpub" pub-id-type="custom">morpho-915</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="section-heading" xml:lang="ru"><subject>ОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯ</subject></subj-group><subj-group subj-group-type="section-heading" xml:lang="en"><subject>RESEARCH ARTICLES</subject></subj-group></article-categories><title-group><article-title>ИММУНОГИСТОХИМИЧЕСКОЕ ИССЛЕДОВАНИЕ MTOR+-ФИБРОБЛАСТОВ В ДИНАМИКЕ РАЗВИТИЯ И СТАРЕНИЯ КОЖИ ЧЕЛОВЕКА</article-title><trans-title-group xml:lang="en"><trans-title>IMMUNOHISTOCHEMICAL STUDY OF MTOR+-FIBROBLASTS IN THE HUMAN SKIN DEVELOPMENT AND AGING DYNAMICS</trans-title></trans-title-group></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0002-5436-1333</contrib-id><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Голубцова</surname><given-names>Наталья Николаевна</given-names></name><name name-style="western" xml:lang="en"><surname>Golubtsova</surname><given-names>Natal'ya N.</given-names></name></name-alternatives><bio xml:lang="ru"><p>доктор биологических наук, доцент, заведующая кафедрой общей и клинической морфологии и судебной медицины</p></bio><bio xml:lang="en"><p>Doctor of Biological Siences, Docent, Head of the  General and Clinical Morphology and Forensic Medicine Department</p></bio><email xlink:type="simple">golubnata@list.ru</email><xref ref-type="aff" rid="aff-1"/></contrib><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">https://orcid.org/0009-0007-5937-1315</contrib-id><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Прокопьева</surname><given-names>Татьяна Николаевна</given-names></name><name name-style="western" xml:lang="en"><surname>Prokop'eva</surname><given-names>Tat'yana N.</given-names></name></name-alternatives><bio xml:lang="ru"><p>старший преподаватель кафедры общей и клинической морфологии и судебной медицины</p></bio><bio xml:lang="en"><p>Senior Lecturer of the  General and Clinical Morphology and Forensic Medicine Department</p></bio><email xlink:type="simple">doctor.geriatr@gmail.com</email><xref ref-type="aff" rid="aff-1"/></contrib></contrib-group><aff-alternatives id="aff-1"><aff xml:lang="ru"><institution>Чувашский государственный университет имени И.Н. Ульянова, Чебоксары</institution><country>Россия</country></aff><aff xml:lang="en"><institution>Ulyanov Chuvash State University, Cheboksary</institution><country>Russian Federation</country></aff></aff-alternatives><pub-date pub-type="collection"><year>2024</year></pub-date><pub-date pub-type="epub"><day>17</day><month>12</month><year>2024</year></pub-date><volume>32</volume><issue>4</issue><elocation-id>id-915 Cтатья опубликована / The Article is published</elocation-id><permissions><copyright-statement>Copyright &amp;#x00A9; Голубцова Н.Н., Прокопьева Т.Н., 2024</copyright-statement><copyright-year>2024</copyright-year><copyright-holder xml:lang="ru">Голубцова Н.Н., Прокопьева Т.Н.</copyright-holder><copyright-holder xml:lang="en">Golubtsova N.N., Prokop'eva T.N.</copyright-holder><license xml:lang="ru" license-type="creative-commons-attribution" xlink:href="https://creativecommons.org/licenses/by/4.0/" xlink:type="simple"><license-p>Данная работа распространяется под лицензией Creative Commons Attribution 4.0.</license-p></license><license xml:lang="en" license-type="creative-commons-attribution" xlink:href="https://creativecommons.org/licenses/by/4.0/" xlink:type="simple"><license-p>This work is licensed under a Creative Commons Attribution 4.0 License.</license-p></license></permissions><self-uri xlink:href="https://www.morpholetter.com/jour/article/view/915">https://www.morpholetter.com/jour/article/view/915</self-uri><abstract><p>Путь мишени рапамицина у млекопитающих (mTOR) является важным клеточным сигнальным путем, участвующим в ряде важных физиологических функций, включая рост клеток, пролиферацию, метаболизм, синтез белка и аутофагию в ответ на различные внешние стимулы. Сигнальный путь mTOR существенно влияет на процессы старения в организме, регулируя клеточные функции и адаптацию к стрессовым условиям, но его значение для развития и физиологического старения кожи человека остается недостаточно изученным и открывает перспективы для дальнейших исследований. Цель исследования – изучение динамики изменений доли mTOR+-фибробластов в дерме человека в процессе развития и старения кожи и определение возможной роли mTOR в регуляции численности и пролиферативной активности фибробластов в процессе ее возрастных изменений. В качестве материала для исследования использованы 114 препаратов кожи случаев аутопсий различного возраста. Образцы кожи представляли собой аутоптаты нижней части передней поверхности шеи, полученные у плодов, начиная с 20 недели беременности, и людей, от рождения до 85 лет. MTOR+-, PCNA+- и виментин+-фибробласты изучали на фиксированных формалином срезах иммуногистохимическим методом. Полученные результаты позволяют заключить, что в коже плодов достоверно больше mTOR+-фибробластов, по сравнению с кожей людей от рождения до 85 лет. Доля фибробластов экспрессирующих mTOR в дерме человека статистически достоверно уменьшается с 20-недельного возраста до 60 лет с 95% до 78%, что доказывает значение фактора возраста в содержании mTOR+-фибробластов в дерме человека. В постнатальный период наблюдается постепенное уменьшение доли mTOR+-фибробластов. Отрицательная динамика возрастных изменений доли mTOR+-фибробластов в дерме начиная с фетального периода развития до 60 лет однонаправлена с возрастной динамикой общего числа и пролиферативной активности фибробластов. Таким образом, получены доказательства возрастной специфики участия mTOR в регуляции пролиферации фибробластов в дерме кожи человека.</p></abstract><trans-abstract xml:lang="en"><p>The mammalian target of rapamycin (mTOR) pathway is an important cellular signaling pathway involved in a number of important physiological functions, including cell growth, proliferation, metabolism, protein synthesis and autophagy in response to various external stimuli. The mTOR signaling pathway significantly affects the aging process in the body, regulating cellular functions and adaptation to stressful conditions, but its significance for the development and physiological aging of human skin remains poorly understood and opens up prospects for further research. The aim of the study was to study the dynamics of changes in the proportion of mTOR+-fibroblasts in the human dermis during skin development and aging and to determine the possible role of mTOR in regulating the number and proliferative activity of fibroblasts during its age-related changes. The study material included 114 skin preparations from autopsy cases of different ages. The skin samples were autopsies of the lower part of the anterior neck surface obtained from fetuses starting from the 20th week of pregnancy and from humans from birth to 85 years of age. MTOR+-, PCNA+- and vimentin+-fibroblasts were studied on formalin-fixed sections using the immunohistochemical method. The results obtained allow us to conclude that the skin of fetuses contains significantly more mTOR+-fibroblasts than the skin of humans from birth to 85 years of age. The proportion of fibroblasts expressing mTOR in the human dermis statistically significantly decreases from the age of 20 weeks to 60 years from 95% to 78%, which proves the importance of the age factor in the content of mTOR+-fibroblasts in the human dermis. In the postnatal period, a gradual decrease in the proportion of mTOR+-fibroblasts is observed. The negative dynamics of age-related changes in the proportion of mTOR+-fibroblasts in the dermis from the fetal period to 60 years of age is in the same direction as the age-related dynamics of the total number and proliferative activity of fibroblasts. Thus, evidence has been obtained for the age-specificity of mTOR participation in the regulation of fibroblast proliferation in the dermis of human skin.</p></trans-abstract><kwd-group xml:lang="ru"><kwd>кожа</kwd><kwd>фибробласты</kwd><kwd>mTOR</kwd><kwd>PCNA</kwd><kwd>виментин</kwd><kwd>фибробласты</kwd><kwd>старение</kwd></kwd-group><kwd-group xml:lang="en"><kwd>skin</kwd><kwd>fibroblasts</kwd><kwd>mTOR</kwd><kwd>PCNA</kwd><kwd>vimentin</kwd><kwd>fibroblasts</kwd><kwd>aging</kwd></kwd-group><funding-group><funding-statement xml:lang="ru">Исследование выполнено при финансовой поддержке грантом научных школ Чувашского государственного университета имени И.Н. Ульянова</funding-statement><funding-statement xml:lang="en">The study was carried out with financial support by the grant from the scientific schools of the Ulyanov Chuvash State University</funding-statement></funding-group></article-meta></front><back><ref-list><title>References</title><ref id="cit1"><label>1</label><citation-alternatives><mixed-citation xml:lang="ru">Ali ES, Mitra K, Akter S, et al. Recent advances and limitations of mTOR inhibitors in the treatment of cancer. Cancer Cell Int. 2022;22(1):284. https://doi.org/10.1186/s12935-022-02706-8</mixed-citation><mixed-citation xml:lang="en">Ali ES, Mitra K, Akter S, et al. Recent advances and limitations of mTOR inhibitors in the treatment of cancer. Cancer Cell Int. 2022;22(1):284. https://doi.org/10.1186/s12935-022-02706-8</mixed-citation></citation-alternatives></ref><ref id="cit2"><label>2</label><citation-alternatives><mixed-citation xml:lang="ru">Buddham R, Chauhan S, Narad P et al. Reconstruction and Exploratory Analysis of mTORC1 Signaling Pathway and Its Applications to Various Diseases Using Network-Based Approach. J Microbiol Biotechnol. 2022;32(3):365-377. https://doi.org/10.4014/jmb.2108.08007</mixed-citation><mixed-citation xml:lang="en">Buddham R, Chauhan S, Narad P et al. Reconstruction and Exploratory Analysis of mTORC1 Signaling Pathway and Its Applications to Various Diseases Using Network-Based Approach. J Microbiol Biotechnol. 2022;32(3):365-377. https://doi.org/10.4014/jmb.2108.08007</mixed-citation></citation-alternatives></ref><ref id="cit3"><label>3</label><citation-alternatives><mixed-citation xml:lang="ru">Wu M, Cong Y, Wang K et al. Bisphenol A impairs macrophages through inhibiting autophagy via AMPK/mTOR signaling pathway and inducing apoptosis. Ecotoxicol Environ Saf. 2022;234:113395. https://doi.org/ 10.1016/j.ecoenv.2022.113395</mixed-citation><mixed-citation xml:lang="en">Wu M, Cong Y, Wang K et al. Bisphenol A impairs macrophages through inhibiting autophagy via AMPK/mTOR signaling pathway and inducing apoptosis. Ecotoxicol Environ Saf. 2022;234:113395. https://doi.org/ 10.1016/j.ecoenv.2022.113395</mixed-citation></citation-alternatives></ref><ref id="cit4"><label>4</label><citation-alternatives><mixed-citation xml:lang="ru">Gunin AG, Petrov VV, Golubtzova NN et al. Age-related changes in angiogenesis in human dermis. Exp Gerontol. 2014;55:143-151. https://doi.org/10.1016/j.exger.2014.04.010</mixed-citation><mixed-citation xml:lang="en">Gunin AG, Petrov VV, Golubtzova NN et al. Age-related changes in angiogenesis in human dermis. Exp Gerontol. 2014;55:143-151. https://doi.org/10.1016/j.exger.2014.04.010</mixed-citation></citation-alternatives></ref><ref id="cit5"><label>5</label><citation-alternatives><mixed-citation xml:lang="ru">Holroyd AK, Michie AM. The role of mTOR-mediated signaling in the regulation of cellular migration. Immunol Lett. 2018;196:74-79. https://doi.org/10.1016/j.imlet.2018.01.015</mixed-citation><mixed-citation xml:lang="en">Holroyd AK, Michie AM. The role of mTOR-mediated signaling in the regulation of cellular migration. Immunol Lett. 2018;196:74-79. https://doi.org/10.1016/j.imlet.2018.01.015</mixed-citation></citation-alternatives></ref><ref id="cit6"><label>6</label><citation-alternatives><mixed-citation xml:lang="ru">Jung SH, Hwang HJ, Kang D et al. mTOR kinase leads to PTEN-loss-induced cellular senescence by phosphorylating p53. Oncogene. 2019;38(10):1639-1650. https://doi.org/10.1038/s41388-018-0521-8</mixed-citation><mixed-citation xml:lang="en">Jung SH, Hwang HJ, Kang D et al. mTOR kinase leads to PTEN-loss-induced cellular senescence by phosphorylating p53. Oncogene. 2019;38(10):1639-1650. https://doi.org/10.1038/s41388-018-0521-8</mixed-citation></citation-alternatives></ref><ref id="cit7"><label>7</label><citation-alternatives><mixed-citation xml:lang="ru">Karagianni F, Pavlidis A, Malakou LS et al. Predominant Role of mTOR Signaling in Skin Diseases with Therapeutic Potential. Int J Mol Sci. 2022;23(3):1693. https://doi.org/10.3390/ijms23031693</mixed-citation><mixed-citation xml:lang="en">Karagianni F, Pavlidis A, Malakou LS et al. Predominant Role of mTOR Signaling in Skin Diseases with Therapeutic Potential. Int J Mol Sci. 2022;23(3):1693. https://doi.org/10.3390/ijms23031693</mixed-citation></citation-alternatives></ref><ref id="cit8"><label>8</label><citation-alternatives><mixed-citation xml:lang="ru">Liu GY, Sabatini DM. mTOR at the nexus of nutrition, growth, ageing and disease. Nat Rev Mol Cell Biol. 2020r;21(4):183-203. https://doi.org/10.1038/s41580-019-0199-y</mixed-citation><mixed-citation xml:lang="en">Liu GY, Sabatini DM. mTOR at the nexus of nutrition, growth, ageing and disease. Nat Rev Mol Cell Biol. 2020r;21(4):183-203. https://doi.org/10.1038/s41580-019-0199-y</mixed-citation></citation-alternatives></ref><ref id="cit9"><label>9</label><citation-alternatives><mixed-citation xml:lang="ru">Liu P, Chen H, Yan L et al. Laminin α5 modulates fibroblast proliferation in epidural fibrosis through the PI3K/AKT/mTOR signaling path-way. Mol Med Rep. 2020;21(3):1491-1500. https://doi.org/10.3892/mmr.2020.10967</mixed-citation><mixed-citation xml:lang="en">Liu P, Chen H, Yan L et al. Laminin α5 modulates fibroblast proliferation in epidural fibrosis through the PI3K/AKT/mTOR signaling path-way. Mol Med Rep. 2020;21(3):1491-1500. https://doi.org/10.3892/mmr.2020.10967</mixed-citation></citation-alternatives></ref><ref id="cit10"><label>10</label><citation-alternatives><mixed-citation xml:lang="ru">Qin D, Ren R, Jia C et al. Rapamycin Protects Skin Fibroblasts from Ultraviolet B-Induced Photoaging by Suppressing the Production of Reactive Oxygen Species. Cell Physiol Biochem. 2018;46(5):1849-1860. https://doi.org/10.1159/000489369</mixed-citation><mixed-citation xml:lang="en">Qin D, Ren R, Jia C et al. Rapamycin Protects Skin Fibroblasts from Ultraviolet B-Induced Photoaging by Suppressing the Production of Reactive Oxygen Species. Cell Physiol Biochem. 2018;46(5):1849-1860. https://doi.org/10.1159/000489369</mixed-citation></citation-alternatives></ref><ref id="cit11"><label>11</label><citation-alternatives><mixed-citation xml:lang="ru">Panwar V, Singh A, Bhatt M et al. Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease. Signal Transduct Target Ther. 2023;8(1):375. https://doi.org/10.1038/s41392-023-01608-z</mixed-citation><mixed-citation xml:lang="en">Panwar V, Singh A, Bhatt M et al. Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease. Signal Transduct Target Ther. 2023;8(1):375. https://doi.org/10.1038/s41392-023-01608-z</mixed-citation></citation-alternatives></ref><ref id="cit12"><label>12</label><citation-alternatives><mixed-citation xml:lang="ru">Walters HE, Cox LS. mTORC Inhibitors as Broad-Spectrum Therapeutics for Age-Related Diseases. Int J Mol Sci. 2018;19(8):2325. https://doi.org/10.3390/ijms19082325</mixed-citation><mixed-citation xml:lang="en">Walters HE, Cox LS. mTORC Inhibitors as Broad-Spectrum Therapeutics for Age-Related Diseases. Int J Mol Sci. 2018;19(8):2325. https://doi.org/10.3390/ijms19082325</mixed-citation></citation-alternatives></ref><ref id="cit13"><label>13</label><citation-alternatives><mixed-citation xml:lang="ru">Gunin AG, Golubtzova NN. Changes in the number of p23-positive fibroblasts in human dermis with aging. Adv Gerontol. 2021;34(5):694-700</mixed-citation><mixed-citation xml:lang="en">Gunin AG, Golubtzova NN. Changes in the number of p23-positive fibroblasts in human dermis with aging. Adv Gerontol. 2021;34(5):694-700</mixed-citation></citation-alternatives></ref><ref id="cit14"><label>14</label><citation-alternatives><mixed-citation xml:lang="ru">Szwed A, Kim E, Jacinto E. Regulation and metabolic functions of mTORC1 and mTORC2. Physiol Rev. 2021;101(3):1371-1426. https://doi.org/10.1152/physrev.00026.2020</mixed-citation><mixed-citation xml:lang="en">Szwed A, Kim E, Jacinto E. Regulation and metabolic functions of mTORC1 and mTORC2. Physiol Rev. 2021;101(3):1371-1426. https://doi.org/10.1152/physrev.00026.2020</mixed-citation></citation-alternatives></ref><ref id="cit15"><label>15</label><citation-alternatives><mixed-citation xml:lang="ru">Zhang J, Yu H, Man MQ et al. Aging in the dermis: Fibroblast senescence and its significance. Aging Cell. 2024;23(2):e14054. https://doi.org/10.1111/acel.14054</mixed-citation><mixed-citation xml:lang="en">Zhang J, Yu H, Man MQ et al. Aging in the dermis: Fibroblast senescence and its significance. Aging Cell. 2024;23(2):e14054. https://doi.org/10.1111/acel.14054</mixed-citation></citation-alternatives></ref><ref id="cit16"><label>16</label><citation-alternatives><mixed-citation xml:lang="ru">Jiménez-Uribe AP, Gómez-Sierra T, Aparicio-Trejo OE et al. Backstage players of fibrosis: NOX4, mTOR, HDAC, and S1P; companions of TGF-β. Cell Signal. 2021;87:110123. https://doi.org/10.1016/j.cellsig.2021.110123</mixed-citation><mixed-citation xml:lang="en">Jiménez-Uribe AP, Gómez-Sierra T, Aparicio-Trejo OE et al. Backstage players of fibrosis: NOX4, mTOR, HDAC, and S1P; companions of TGF-β. Cell Signal. 2021;87:110123. https://doi.org/10.1016/j.cellsig.2021.110123</mixed-citation></citation-alternatives></ref><ref id="cit17"><label>17</label><citation-alternatives><mixed-citation xml:lang="ru">Qin Z, Xia W, Fisher GJ, et al. YAP/TAZ regulates TGF-β/Smad3 signaling by induction of Smad7 via AP-1 in human skin dermal fibro-blasts. Cell Commun Signal. 2018;16(1):18. https://doi.org/10.1186/s12964-018-0232-3</mixed-citation><mixed-citation xml:lang="en">Qin Z, Xia W, Fisher GJ, et al. YAP/TAZ regulates TGF-β/Smad3 signaling by induction of Smad7 via AP-1 in human skin dermal fibro-blasts. Cell Commun Signal. 2018;16(1):18. https://doi.org/10.1186/s12964-018-0232-3</mixed-citation></citation-alternatives></ref><ref id="cit18"><label>18</label><citation-alternatives><mixed-citation xml:lang="ru">Chen Q, Zhang H, Yang Y et al. Metformin Attenuates UVA-Induced Skin Photoaging by Suppressing Mitophagy and the PI3K/AKT/mTOR Pathway. Int J Mol Sci. 2022;23(13):6960. https://doi.org/10.3390/ijms23136960</mixed-citation><mixed-citation xml:lang="en">Chen Q, Zhang H, Yang Y et al. Metformin Attenuates UVA-Induced Skin Photoaging by Suppressing Mitophagy and the PI3K/AKT/mTOR Pathway. Int J Mol Sci. 2022;23(13):6960. https://doi.org/10.3390/ijms23136960</mixed-citation></citation-alternatives></ref><ref id="cit19"><label>19</label><citation-alternatives><mixed-citation xml:lang="ru">Wang M, Charareh P, Lei X et al. Autophagy: Multiple Mechanisms to Protect Skin from Ultraviolet Radiation-Driven Photoaging. Oxid Med Cell Longev. 2019;2019:8135985. https://doi.org/10.1155/2019/8135985</mixed-citation><mixed-citation xml:lang="en">Wang M, Charareh P, Lei X et al. Autophagy: Multiple Mechanisms to Protect Skin from Ultraviolet Radiation-Driven Photoaging. Oxid Med Cell Longev. 2019;2019:8135985. https://doi.org/10.1155/2019/8135985</mixed-citation></citation-alternatives></ref><ref id="cit20"><label>20</label><citation-alternatives><mixed-citation xml:lang="ru">Lim GE, Park JE, Cho YH et al. Alpha-neoendorphin can reduce UVB-induced skin photoaging by activating cellular autophagy. Arch Bio-chem Biophys. 2020;689:108437. https://doi.org/10.1016/j.abb.2020.108437</mixed-citation><mixed-citation xml:lang="en">Lim GE, Park JE, Cho YH et al. Alpha-neoendorphin can reduce UVB-induced skin photoaging by activating cellular autophagy. Arch Bio-chem Biophys. 2020;689:108437. https://doi.org/10.1016/j.abb.2020.108437</mixed-citation></citation-alternatives></ref></ref-list><fn-group><fn fn-type="conflict"><p>The authors declare that there are no conflicts of interest present.</p></fn></fn-group></back></article>
